New insights into the pathophysiology of methylmalonic acidemia

Abstract

Methylmalonic acidemia (MMA) is a severe inborn error of metabolism that is characterized by pleiotropic metabolic perturbations and multiorgan pathology. Treatment options are limited and non-curative as the underlying causative molecular mechanisms remain unknown. While earlier studies have focused on the potential direct toxicity of metabolites such as methylmalonic and propionic acid as a mechanism to explain disease pathophysiology, new observations have revealed that aberrant acylation, specifically methylmalonylation, is a characteristic feature of MMA. The mitochondrial sirtuin enzyme SIRT5 is capable of recognizing and removing this PTM, however, reduced protein levels of SIRT5 along with other mitochondrial SIRTs 3 and 4 in MMA and potentially reduced function of all three indicates aberrant acylation may require clinical intervention. Therefore, targeting posttranslational modifications may represent a new therapeutic approach to treat MMA and related organic acidemias.

Organic acidurias: Ingredients for precision medicine

“…This is followed by Ramon et al 6 demonstrating how cellular and computational models help to decipher environmental and metabolic interactions in methylmalonic aciduria, suggesting a compensatory role for increased anaplerosis through glutamine. Next, Head et al 7 outline how precise knowledge about pathophysiology in methylmalonic aciduria has enabled the development of targeted therapy. Since conservative therapy does not prevent disease progression and the manifestation of irreversible organ dysfunction in individuals with methylmalonic and propionic aciduria, two articles presented by Martinelli et al 8 and Chakrapani et al 9 focus on safety, efficacy and timing of solid organ transplantation as well as neurological outcome following transplantation.…”